Novel ilaprazole crystal form and preparation method thereof

Abstract

The invention discloses a novel ilaprazole crystal form. The X-ray diffraction spectrum of crystal powder of the crystal form has the following characteristic peaks expressed by angle 2 theta: 6.7 degrees + / -0.2 degrees, 6.9 degrees + / -0.2 degrees, 12.6 degrees + / -0.2 degrees, 15.8 degrees + / -0.2 degrees, 18.1 degrees + / -0.2 degrees, 21.2 degrees + / -0.2 degrees, 22.1 degrees + / -0.2 degrees, 23.6 degrees + / -0.2 degrees and 25.6 degrees + / -0.2 degrees. The invention also discloses a preparation method of the novel ilaprazole crystal form, which comprises the following steps: dissolving an ilaprazole crude product in a mixed solution of dichloromethane, methanol and triethylamine, decolorizing with activated carbon, adding isopropyl ether for crystallization, centrifuging the obtained solid, and pulping with ethanol and n-heptane. The crystal form of ilaprazole can exist stably and is not prone to moisture absorption, and the crystal form is good in thermal stability, facilitates purification of ilaprazole and is beneficial to storage.

Description

Technical Field

[0001] The present invention relates to the technical field of shaft seal leakage treatment methods, and in particular to a new ilaprazole crystal form and a preparation method thereof. Background Art

[0002] Ilaprazole is a new generation of proton pump inhibitor (PPI), and its chemical structure belongs to the benzimidazole derivatives. The drug was developed by Ilyang Pharmaceutical Co., Ltd. of South Korea and was first launched by Livzon Group.

[0003] Ilaprazole is an irreversible proton pump inhibitor. After oral absorption, it is metabolized into its active product, sulfonamide, which couples with the sulfhydryl group of H+ / K+-ATPase to form an irreversible covalent disulfide bond, blocking the enzyme's H+ / K+ transport mechanism, thereby inhibiting acid secretion.

[0004] The original patent CN101687848B discloses the crystalline forms A, B, E, F and I of the racemic form of ilaprazole. The crystalline forms are characterized by: the X-ray powder diffraction pattern (represented by the 2θ angle) has characteristic peaks at 8.0°±0.2°, 13.2°±0.2° and 24.1°±0.2°.

[0005] In addition to the properties of the drug itself, the stability of the drug's crystallinity can affect solubility, dissolution rate, hardness compressibility, and melting point, which in turn may have an impact on the production and efficacy of the drug. Therefore, the identification of drug crystal forms and methods for their reproducible preparation are now needed in the technical fields of chemistry and therapy.

[0006] Although CN101687848B has reported the crystal form of ilaprazole racemate, new crystal forms of ilaprazole racemate, especially stable new crystal forms having excellent pharmacological activity and suitable for drug formulation, and simple preparation methods are still urgently needed. Summary of the invention

[0007] In view of the above technical problems, the present invention provides a new crystal form of ilaprazole and a preparation method thereof.

[0008] In order to achieve the above object, the technical solution of the present invention is as follows: A new crystalline form of ilaprazole, wherein the crystalline powder X-ray diffraction spectrum of the crystalline form has the following characteristic peaks represented by 2θ angles: 6.7°±0.2°, 6.9°±0.2°, 12.6°±0.2°, 15.8°±0.2°, 18.1°±0.2°, 21.2°±0.2°, 22.1°±0.2°, 23.6°±0.2°, 25.6°±0.2°.

[0009] Among them, the crystalline powder X-ray diffraction spectrum of this crystal form has the following characteristic peaks represented by 2θ angles: 6.7°±0.2°, 6.9°±0.2°, 9.0°±0.2°, 12.6°±0.2°, 14.7°±0.2°, 15.8°±0.2°, 18.1°±0.2°, 19.5°±0.2°, 20.2°±0.2°, 21.2°±0.2°, 22.1°±0.2°, 23.6°±0.2°, 24.1°±0.2°, 25.6°±0.2°, 26.6°±0.2°, 27.1°±0.2°.

[0010] Among them, the DSC peak temperature of ilaprazole is 156.98℃.

[0011] The present invention also provides a method for preparing a new crystal form of ilaprazole, comprising the following steps: dissolving a crude ilaprazole product in a mixed solution of dichloromethane, methanol and triethylamine, decolorizing with activated carbon, adding isopropyl ether for crystallization, centrifuging the obtained solid, and beating with ethanol and n-heptane; Among them, the decolorization time is 10-30min, the crystallization time is 0.5-4 hours, and the crystallization is carried out in the range of 0-10°C; the pulping time is 0.5-2 hours, and the pulping is carried out in the range of 0-10°C; the mass ratio of crude ilaprazole to dichloromethane is 1:(4-10); the mass ratio of crude ilaprazole to methanol is 1:(0.3-0.8); the mass ratio of crude ilaprazole to triethylamine is 1:(0.005-0.0.5); the mass ratio of ilaprazole to isopropyl ether is 1:(10-20); the mass ratio of ilaprazole to ethanol is 1:(5-10); the mass ratio of ethanol to n-heptane is 1:(1.5-2).

[0012] Among them, the decolorization time is 15 minutes, the crystallization time is 2 hours, the beating time is 1 hour, the mass ratio of crude ilaprazole to dichloromethane is 1:6, the mass ratio of crude ilaprazole to methanol is 1:0.5, the mass ratio of crude ilaprazole to triethylamine is 1:0.01, the mass ratio of ilaprazole to isopropyl ether is 1:14.5, the mass ratio of ilaprazole to ethanol is 1:6.4, and the mass ratio of ethanol to n-heptane is 1:1.7.

[0013] Wherein, after the crystallization step, the process further includes filtering and / or drying the crystals; after the pulping step, the process further includes filtering and / or drying the crystals.

[0014] The beneficial effects of the present invention are: 1. The ilaprazole having the crystal form of the present invention can exist stably and is not easy to absorb moisture. The crystal form has good thermal stability, is convenient for purifying ilaprazole, and is conducive to storage.

[0015] 2. Six batches of enteric-coated tablets (12 tablets in each batch) prepared from the same batch of raw and excipients were investigated, and the reproducibility of drug content was tested between batches. The RSD was 3.0%, indicating that the preparation process of the present invention has good reproducibility.

[0016] 3. Twelve tablets of the same batch of products were examined to test the uniformity of drug content, with RSD = 2.9%, indicating that the preparation process of the present invention has good uniformity. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] The present invention is further described below in conjunction with the accompanying drawings and embodiments: Figure 1 1HNMR diagram of the first batch of Example 1; Figure 2 This is the 13CNMR diagram of the first batch of Example 1; Figure 3 This is the DSC graph of the first batch of Example 1; Figure 4 This is the XRD pattern of the first batch of Example 1; Figure 5 This is the XRD pattern of the second batch of Example 1; Figure 6 This is the XRD pattern of the third batch of Example 1; Figure 7 It is the structural formula of the crystal form of the present invention. DETAILED DESCRIPTION

[0018] In order to make the purpose, technical scheme and advantages of the present invention clearer, the present invention is further described in detail below in conjunction with specific embodiments. It should be understood that these descriptions are exemplary only and are not intended to limit the scope of the present invention. In addition, in the following description, the description of known structures and technologies is omitted to avoid unnecessary confusion of the concept of the present invention.

[0019] Example 1 Preparation of new crystalline form of ilaprazole: Add 132.0 kg of dichloromethane and 11.0 kg of methanol to the reactor, start stirring, then add 220.0 g of triethylamine, and finally add 22.0 kg of crude ilaprazole, control the temperature in the reactor to 0-10°C, and stir until the system is dissolved; add 1.1 kg of activated carbon dispersed with 13.9 kg of dichloromethane to the reactor, control the temperature to 0-10°C, stir and decolorize for 15+5 minutes, and then filter to remove the activated carbon, and filter the filtrate into a reactor that has been pre-added with 319.0 kg of isopropyl ether and cooled to 0-10°C, and keep the temperature at 0-10°C and stir to crystallize for 2 hours. Centrifuge the reaction solution to obtain refined ilaprazole. The refined product was slurried with 140.8 kg of medicinal ethanol and 240.5 kg of n-heptane at 0-10° C. for 1 hour and then centrifuged to obtain wet ilaprazole. The wet product was dried at 35-45° C. to obtain 18.99 kg of qualified product with a molar yield of 86.3% and a purity of 99.87%.

[0020] The X-ray powder diffraction spectra of ilaprazole obtained in three parallel batches in this example are as follows Figure 1-Figure 6 As shown, the 2θ angle and relative diffraction intensity of the characteristic peak are shown in the following table: Example 2 Preparation of Ilaprazole Enteric-coated Tablets Plain slices 20 parts of ilaprazole, 500 parts of hydroxypropyl cellulose, 25 parts of magnesium stearate, 5 parts of microcrystalline cellulose, 3 parts of sodium carboxymethyl cellulose, 12 parts of sodium stearyl fumarate, 22 parts of micropowder silica gel, and 66 parts of 8% by mass povidone K30 ethanol solution.

[0021] Coating liquid Glue A: 200g shellac, 20ml castor oil, add anhydrous ethanol to 1000ml; Glue B: 1000g of acrylic resin No. 2, 50ml of diethyl phthalate, 100ml of castor oil, 50ml of Tween-80, 150g of talcum powder, 1-3g of pigment, add anhydrous ethanol to 5000ml.

[0022] Mix before use, the volume ratio of A glue and B glue is 1:3.

[0023] Preparation process: Weigh ilaprazole, magnesium stearate, microcrystalline cellulose, sodium carboxymethyl cellulose, and hydroxypropyl cellulose according to the prescribed amount, put them into a granulator, and stir and mix them evenly; add 8% by weight of povidone K30 ethanol solution, continue stirring, granulate, and pass through a 20-mesh nylon sieve to form wet granules; dry the prepared wet granules and granulate them; add sodium stearyl fumarate and micro-powder silica gel, mix them evenly, and press them into tablets to obtain plain tablets; After the plain tablets are wiped of fine powder, they are placed in a coating pan for preheating. The speed of the coating pan is slowly increased to 25rpm. The prepared coating solution is slowly sprayed on the rotating tablet surface. The air inlet temperature is controlled at 40-45℃, the spray pressure is 2-3kg / cm2, and the speed of the coating pan is 25rpm. The tablet bed temperature is kept constant during the coating process. In order to prevent water infiltration and tablet core wear at the beginning, hot air drying and spraying are carried out alternately. After a clear coating film is formed on the surface, continuous spraying can be carried out until the coating film increases to the specified weight; after spraying, continue to dry with hot air for ten minutes, and then cool to room temperature. The coated tablets are placed in a 45℃ oven and dried for 3 hours.

[0024] Process reproducibility and uniformity test: Six batches of enteric-coated tablets (12 tablets in each batch) prepared from the same batch of raw and excipients were investigated, and the reproducibility of drug content was tested between batches, with RSD = 3.0%, indicating that the preparation process of the present invention has good reproducibility.

[0025] Twelve tablets of the same batch of products were examined to test the uniformity of drug content, with RSD = 2.9%, indicating that the preparation process of the present invention has good uniformity.

[0026] Example 3 like Figure 7 As shown, a new crystalline form of ilaprazole has a crystalline powder X-ray diffraction spectrum having the following characteristic peaks represented by 2θ angles: 6.7°±0.2°, 6.9°±0.2°, 12.6°±0.2°, 15.8°±0.2°, 18.1°±0.2°, 21.2°±0.2°, 22.1°±0.2°, 23.6°±0.2°, 25.6°±0.2°.

[0027] Among them, the DSC peak temperature of ilaprazole is 156.98℃.

[0028] The present invention also provides a method for preparing a new crystal form of ilaprazole, comprising the following steps: dissolving a crude ilaprazole product in a mixed solution of dichloromethane, methanol and triethylamine, decolorizing with activated carbon, adding isopropyl ether for crystallization, centrifuging the obtained solid, and beating with ethanol and n-heptane; Among them, the decolorization time is 10 minutes, the crystallization time is 0.5 hours, and the crystallization is carried out in the range of 0-10°C; the beating time is 0.5 hours, and the beating is carried out in the range of 0-10°C; the mass ratio of crude ilaprazole to dichloromethane is 1:4; the mass ratio of crude ilaprazole to methanol is 1:0.3; the mass ratio of crude ilaprazole to triethylamine is 1:0.005; the mass ratio of ilaprazole to isopropyl ether is 1:10; the mass ratio of ilaprazole to ethanol is 1:5; the mass ratio of ethanol to n-heptane is 1:1.5.

[0029] Wherein, after the crystallization step, there is also a step of filtering the crystals; after the pulping step, there is also a step of filtering the crystals.

[0030] Example 4 like Figure 7 As shown, a new crystalline form of ilaprazole has a crystalline powder X-ray diffraction spectrum having the following characteristic peaks represented by 2θ angles: 6.7°±0.2°, 6.9°±0.2°, 12.6°±0.2°, 15.8°±0.2°, 18.1°±0.2°, 21.2°±0.2°, 22.1°±0.2°, 23.6°±0.2°, 25.6°±0.2°.

[0031] Among them, the DSC peak temperature of ilaprazole is 156.98℃.

[0032] The present invention also provides a method for preparing a new crystal form of ilaprazole, comprising the following steps: dissolving a crude ilaprazole product in a mixed solution of dichloromethane, methanol and triethylamine, decolorizing with activated carbon, adding isopropyl ether for crystallization, centrifuging the obtained solid, and beating with ethanol and n-heptane; Among them, the decolorization time is 30 minutes, the crystallization time is 4 hours, and the crystallization is carried out in the range of 0-10°C; the pulping time is 2 hours, and the pulping is carried out in the range of 0-10°C; the mass ratio of crude ilaprazole to dichloromethane is 1: 10; the mass ratio of crude ilaprazole to methanol is 1: 0.8; the mass ratio of crude ilaprazole to triethylamine is 1: 0.0.5; the mass ratio of ilaprazole to isopropyl ether is 1: 20; the mass ratio of ilaprazole to ethanol is 1: 10; the mass ratio of ethanol to n-heptane is 1: 2.

[0033] Wherein, the step of drying the crystals is further included after the crystallization step; and the step of drying the crystals is further included after the slurrying step.

[0034] Example 5 like Figure 7 As shown, a new crystalline form of ilaprazole has a crystalline powder X-ray diffraction spectrum having the following characteristic peaks represented by 2θ angles: 6.7°±0.2°, 6.9°±0.2°, 9.0°±0.2°, 12.6°±0.2°, 14.7°±0.2°, 15.8°±0.2°, 18.1°±0.2°, 19.5°±0.2°, 20.2°±0.2°, 21.2°±0.2°, 22.1°±0.2°, 23.6°±0.2°, 24.1°±0.2°, 25.6°±0.2°, 26.6°±0.2°, 27.1°±0.2°.

[0035] Among them, the DSC peak temperature of ilaprazole is 156.98℃.

[0036] The present invention also provides a method for preparing a new crystal form of ilaprazole, comprising the following steps: dissolving a crude ilaprazole product in a mixed solution of dichloromethane, methanol and triethylamine, decolorizing with activated carbon, adding isopropyl ether for crystallization, centrifuging the obtained solid, and beating with ethanol and n-heptane; Among them, the decolorization time is 15 minutes, the crystallization time is 2 hours, the beating time is 1 hour, the mass ratio of crude ilaprazole to dichloromethane is 1:6, the mass ratio of crude ilaprazole to methanol is 1:0.5, the mass ratio of crude ilaprazole to triethylamine is 1:0.01, the mass ratio of ilaprazole to isopropyl ether is 1:14.5, the mass ratio of ilaprazole to ethanol is 1:6.4, and the mass ratio of ethanol to n-heptane is 1:1.7.

[0037] Wherein, after the crystallization step, the method further includes the steps of filtering and drying the crystals; after the pulping step, the method further includes the steps of filtering and drying the crystals.

[0038] It should be understood that the above specific embodiments of the present invention are only used to illustrate or explain the principles of the present invention, and do not constitute a limitation of the present invention. Therefore, any modifications, equivalent substitutions, improvements, etc. made without departing from the spirit and scope of the present invention should be included in the protection scope of the present invention. In addition, the appended claims of the present invention are intended to cover all changes and modifications that fall within the scope and boundaries of the appended claims, or the equivalent forms of such scope and boundaries.

Claims

1. A new crystal form of ilaprazole, characterized in that: The crystalline powder X-ray diffraction spectrum of this crystal form has the following characteristic peaks represented by 2θ angles: 6.7°±0.2°, 6.9°±0.2°, 12.6°±0.2°, 15.8°±0.2°, 18.1°±0.2°, 21.2°±0.2°, 22.1°±0.2°, 23.6°±0.2°, 25.6°±0.2°.

2. The new crystalline form of ilaprazole according to claim 1, characterized in that: The crystalline powder X-ray diffraction spectrum of this crystal form has the following characteristic peaks represented by 2θ angles: 6.7°±0.2°, 6.9°±0.2°, 9.0°±0.2°, 12.6°±0.2°, 14.7°±0.2°, 15.8°±0.2°, 18.1°±0.2°, 19.5°±0.2°, 20.2°±0.2°, 21.2°±0.2°, 22.1°±0.2°, 23.6°±0.2°, 24.1°±0.2°, 25.6°±0.2°, 26.6°±0.2°, 27.1°±0.2°.

3. The new crystalline form of ilaprazole according to claim 1, characterized in that: The DSC peak temperature of ilaprazole was 156.98°C.

4. A method for preparing the new crystalline form of ilaprazole as claimed in claim 1 or 2, characterized in that: The following steps are involved: The crude ilaprazole was dissolved in a mixed solution of dichloromethane, methanol and triethylamine, decolorized with activated carbon and then crystallized with isopropyl ether, and the obtained solid was centrifuged and slurried with ethanol and n-heptane; Among them, the decolorization time is 10-30min, the crystallization time is 0.5-4 hours, and the crystallization is carried out in the range of 0-10°C; the pulping time is 0.5-2 hours, and the pulping is carried out in the range of 0-10°C; the mass ratio of crude ilaprazole to dichloromethane is 1:(4-10); the mass ratio of crude ilaprazole to methanol is 1:(0.3-0.8); the mass ratio of crude ilaprazole to triethylamine is 1:(0.005-0.0.5); the mass ratio of ilaprazole to isopropyl ether is 1:(10-20); the mass ratio of ilaprazole to ethanol is 1:(5-10); the mass ratio of ethanol to n-heptane is 1:(1.5-2).

5. The method for preparing a new crystal form of ilaprazole according to claim 4, characterized in that: The decolorization time is 15 minutes, the crystallization time is 2 hours, the beating time is 1 hour, the mass ratio of crude ilaprazole to dichloromethane is 1:6, the mass ratio of crude ilaprazole to methanol is 1:0.5, the mass ratio of crude ilaprazole to triethylamine is 1:0.01, the mass ratio of ilaprazole to isopropyl ether is 1:14.5, the mass ratio of ilaprazole to ethanol is 1:6.4, and the mass ratio of ethanol to n-heptane is 1:1.

7.

6. The method for preparing a new crystal form of ilaprazole according to claim 4, characterized in that: The crystallization step also includes a step of filtering and / or drying the crystals; and the slurrying step also includes a step of filtering and / or drying the crystals.

Images